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Title Flash chemistry: flow chemistry that cannot be done in batch.

Author(s) Yoshida, Jun-ichi; Takahashi, Yusuke; Nagaki, Aiichiro

Citation Chemical communications (2013), 49(85): 9896-9904

Issue Date 2013-11-04

URL http://hdl.handle.net/2433/192988

Right © The Royal Society of Chemistry 2013

Type Journal Article

Textversion author

Kyoto University Chemical Communications Dynamic Article Links ►

Cite this: DOI: 10.1039/c0xx00000x www.rsc.org/xxxxxx Feature Article

Flash chemistry: Flow chemistry that cannot be done in batch† Jun-ichi Yoshida,* Yusuke Takahashi, and Aiichiro Nagaki

Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x

5 Flash chemistry based on high-resolution reaction time for extremely fast reactions involving highly reactive unstable control using flow microreactors enables chemical reactions species on a preparative scale on time scales of a second or less, 55 which cannot be achieved by batch chemistry. that cannot be done in batch and serves as powerful tools for

laboratory synthesis of organic compounds and production in High-resolution reaction time control chemical and pharmaceutical industries. In a flow reactor, the reaction proceeds as a reactant travels through the reactor. Therefore, the concentration of a reactant 10 60 decreases with an increase in the distance from the inlet of the From new materials to new medicinal agents, the central role reactor (Figure 1). The concentration of a product increases and of organic synthesis is expanding nowadays. Driven by reaches a maximum at the outlet of the reactor if overreaction or remarkable improvements in our understanding of factors decomposition of the product does not occur. It is also important governing organic reactions and by increasingly powerful to note that the concentrations of a reactant and a product do not 15 instrumentation and analytical tools, the influence of organic 65 change with the progress of operation time in a steady state. synthesis has been extended to virtually all areas of science.1 Therefore, the reaction time in a flow reactor can correlate to the We usually run reactions in batch reactors such as flasks for space position inside of the reactor. This means that the reaction synthesis in chemistry laboratories. This is presumably because time can be controlled by adjusting the length of a flow reactor, batch reactors are easy to handle for us. Another advantage of although the reaction time also changes with the flow speed. 20 batch reactors is that it is easy for us to imagine how a reaction 70 proceeds in them. When we add a reagent or a catalyst to a solution of a starting material in a flask, a reaction starts. In some cases, we heat a mixture to initiate a reaction. Most of the reactions that we are using for organic synthesis were developed 25 in flasks, and it is not too much to say that organic chemists have been studying flask chemistry. Flask chemistry is chemistry under the constraint of the flask. It should be noted, however, that there are other type of reactors, continuous flow reactors.2,3,4 Recently, it became 30 possible to conduct chemical reactions in a flow reactor in laboratory synthesis. Although large-scale productions of heavy chemicals in the industry have been carried out in continuous flow systems, the use of flow reactors in the production of fine chemical and pharmaceutical industry has just started recently.

35 Continuous flow synthesis is usually carried out using channel- or tube-type reactors. Starting materials and reagents are Figure 1. Reaction profile in a flow reactor fed at the inlets of the reactor by pumping. There are several advantages of continuous flow synthesis in comparison with 75 The length of time that the solution remains in the reactor is batch synthesis. For example, continuous flow processes are called the residence time. Therefore, the reaction time can be 40 generally more suitable for automation than batch processes. controlled by the residence time. One of the most advantageous Because solutions of a starting material and a reagent are fed by features of flow reactors is precise residence time control by pumps, on/off of the flow and the flow rate can be easily changed adjusting the length of the channel or tube and the flow speed. and programmed by a computer. Switching of bulbs enables 80 This leads to precise reaction time control. reactions of various combinations of substrates and reagents in a 5 The residence time or reaction time can be greatly reduced by 45 sequential way. Flow synthesis enables the use of hazardous 6 shortening the length of the channel or tube. By increasing the chemicals safely. Dangerous reactions can be done in a flow speed, the residence time can also be reduced. For example, controlled way under continuous flow mode. However, there is the mean residence time in a flow reactor of the length of 10 mm another important feature of flow chemistry. Flow chemistry 85 at the flow speed of 1 m/s is calculated to be 10 ms (Figure 2). enables reactions that cannot be done in batch, opening a new Although there exists the distribution of the residence time, 50 possibility of chemical synthesis. In this feature article we focus hereafter we consider only the mean residence time for simplicity on the development of such a field of flow chemistry, which is of the discussion. If we want to reduce the reaction time to 5 ms, called flash chemistry.7 Flash chemistry offers integrated scheme

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we just simply need to reduce the length of the reactor to 5 mm. To get better mixing we have to use micromixers.9,10 In micromixers, the solutions to be mixed are distributed into several segments of flows of small width using the microstructure of the device. Mixing takes place in the resulting stream through 55 the interfaces of the segments of flows by virtue of the short diffusion path, and a homogeneous solution is produced in a short period (Figure 4). According to the theory of molecular diffusion, mixing times can be reduced to millisecond order if the width of flows are reduced to micrometer order. This is indeed the case. 60 Although T-shaped micromixers are very simple in structure and are easy to fabricate by conventional mechanical machining 5 Figure 2. Relationship between the length of a flow reactor and the residence time. technology, they can be very effective in achieving fast mixing if the flow speed is high (Figure 4). At a low flow speed, mixing Reactions are often started by mixing two reaction components efficiency is rather low because of the laminar flow regime. and are stopped by adding a quenching reagent. Therefore, the 65 However, when the flow speed exceeds a critical value, the intensity of mixing increases significantly. The engulfment flow 10 reaction time is defined as the time between the first mixing and 11 the mixing with a quenching reagent. In a flow reactor, the regime caused by stream energy seems to be responsible for fast reaction time is defined as the residence time between a reagent mixing. The threshold velocity depends on the size and shape of 12 inlet and the position of the quencher inlet, and can be precisely the microchannels. The reduced possibility of clogging is also controlled by adjusting the length between these positions (Figure 70 an advantage of simple T-shaped micromixers, because the channel size is large compared with multilaminationtype 15 3). micromixers. T-shaped micromixers with 250–500 m inner diameter are popular.

Figure 3. Control of reaction time by adjusting the residence time 20 between the introduction of a reagent and a quenching reagent with fast mixing. 75 Figure 4. T-shaped micromixer Can we control the reaction time by adjusting the length of a

macro flow reactor and flow speed? Yes, the above discussion Thus, flow systems consisting of micromixers and 25 can be applied not only to flow microreactors but also to flow microreactors are quite effective for precise control of reaction macroreactors, if the reaction time is relatively long. However, 80 times on the time scales of a second or less. The feature of short micro is essential for the control of reaction time of extremely and precise reaction time control is extremely useful in fast reactions. Why is micro necessary? The residence time can controlling reactions involving unstable short-lived reactive be greatly reduced to millisecond order by reducing the length of intermediates. This feature is also useful for conducting reactions 30 a microchannel or a microtube in a flow microreactor system. giving products that are unstable under the reaction conditions. However, the lengths of reactors are usually not on micrometer 85 order, but on centimeter order. The micro is necessary for mixing.

If we wish to adjust the reaction time to 1 s, the time for mixing a substrate and a reagent should be much less than 1 s. The same is Control of fast consecutive reactions involving unstable intermediates 35 true for the quenching. Such fast mixing is only possible using We often encounter a problem of control of consecutive micro structures. Mixing occurs because of molecular diffusion. 90 reactions. Let us consider a simple consecutive reaction shown in The time needed for molecular diffusion is proportional to the Scheme 1. S is a substrate (reactant), I is an unstable intermediate, square of the length of the diffusion path. The marked shortening and B is an undesired by-product produced by decomposition of I. of the diffusion path in micromixers results in a mixing speed Intermediate I is transformed to a desired product P by adding a 40 unobtainable in a macroreactor. Therefore, micro is essential for quenching agent before decomposition of I. For simplicity, we the control of reaction time, which ranges from milliseconds to 95 assume a sequence of first-order processes (rate constants: k1 and second time scale. k2). We also assume that the quenching reaction of I to obtain P is How does mixing take place in batch reactors by stirring? much faster than its decomposition to give B. Mixing in a solution phase is defined as a phenomenon that

45 creates homogeneity of all species in the solution. One might think that such homogeneity is achieved immediately after two solutions are combined with vigorous stirring, but this is not true. It takes time (usually 0.01 – several seconds) to achieve homogeneity even with maximum turbulence produced by 8 50 vigorous stirring.

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100 80 60

[%] 40 20 0 Scheme 1. A general scheme of consecutive reactions 0.0 0.5 1.0 1.5 2.0 time [s] Figure 6. A variation of the concentrations of reaction When k2 is much smaller than k1, we can see that the reaction -1 40 components against time (k1 = 10 s and k2/k1 = 0.01). 5 S → I takes place first and goes nearly to completion before the reaction of I → B occurs. After completion of the reaction S → I, the addition of a quenching agent leads to the production of Temperature–residence time map desired product P in good yield. We can add a quenching agent In the previous section, we discussed the importance of the over a wide range of reaction times to get a good yield of P. The residence time control in reactions involving unstable 45 intermediates. The following study on the deprotonation of 10 increase in the reaction rates k2 changes the situation even if k2 is styrene oxide with s-BuLi followed by trapping of the resulting smaller than k1. The reaction S → I takes place first, but before its completion the reaction I → B occurs. I is accumulated in -phenyloxiranyllithium (1) with iodomethane demonstrates the acceptable yields only over a limited time range. power of our approach based on the concept of flash chemistry -1 13 Let us consider the case where k1 = 10 h and k2/k1 = 0.01. As (Figure 7) . Although 1 could be generated from styrene oxide o 50 using t-BuLi or s-BuLi in the presence of TMEDA at –98 C in a 15 shown in Figure 5, S is consumed within 0.5 h. The concentration 14 of P increases with an increase in reaction time and then conventional batch reactor, the use of s-BuLi in the absence of o decreases gradually because of the formation of B. The reaction TMEDA caused decomposition even at –98 C. A flow time should be longer than ca. 0.25 h and should be shorter than microreactor enables us to conduct the transformation at higher o ca. 0.6 h to get a yield higher than 90%. This is easy to do with temperatures such as ca. –70 C.

55 20 batch reactors such as flasks. We need to add a quenching agent ca. 0.5 h after we started the reaction.

100 80 60 Figure 7. Deprotonation of styrene oxide with s-BuLi followed [%] 40 by the reaction with iodomethane in a flow microreactor system. 20 60 0 The reaction profile at –68 oC is shown in Figure 8. By 0.0 0.5 1.0 1.5 2.0 choosing an appropriate residence time for quenching (addition of time [s] iodomethane), methylated product 2 was obtained in a high yield. Figure 5. A variation of the concentrations of reaction -1 25 components against time (k1 = 10 h and k2/k1 = 0.01).

When the reaction is much faster, the reaction cannot be done -1 100 in a controlled way in batch. For example, when k1 = 10 s and k2/k1 = 0.01, the reaction time should be longer than ca. 0.25 s 80

30 and should be shorter than ca. 0.6 s to get a yield higher than 90% 60 as shown in Figure 6. This means a quenching agent should be added precisely in this time domain. Otherwise we cannot get the 40 desired product P in good yield. It should be noted that this kind 20 of high-resolution reaction-time control cannot be achieved in 0 35 flask chemistry. For this purpose the use of a flow microreactor 0 5 10 15 20 25 system equipped with micromixers is essential. 65

Figure 8. Plots of the amount of unchanged styrene oxide and the yield of the methylated product against the residence time (tR) at –68 oC. 70 Because the rates of reactions generally depend on the temperature, temperature control is also important. Therefore, we invented a tool for analyzing reactions based on temperature– residence time map.

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In Figure 9 the conversions of the styrene oxide are plotted how it can help to simplify the synthesis of useful organic against the temperature and the logarithm of the residence time. compounds. At low temperatures and short residence times, the conversion is 40 low and the starting material remained unchanged. The A new approach to protecting-group-free synthesis 5 conversion increases with an increase in the temperature and the Recently, the construction of complicated organic molecules residence time, and the quantitative conversion is obtained at a without using protecting groups (protecting-group-free high temperature–long residence time region. synthesis)15 especially from the viewpoints of atom economy,16 17 18 45 step economy, and redox economy has received significant research interest in the context of ideal synthesis19 and green sustainable chemistry.20 Generally, skeleton-building steps are the most difficult to avoid using protecting groups because such steps often use strongly basic nucleophilic reagents. Among such 50 reagents, organolithium reagents are the most reactive. Therefore, the present approach based on control of the residence time in a flow microreactor serves as a powerful method for protecting- group-free synthesis using organolithium reagents, which is complementary to other approaches using less reactive and more 55 chemoselective reagents. Organolithium species are most reactive organometallic 21 species among those commonly used in organic synthesis, and Figure 9. Contour plots with scatter overlay of the amount of the addition of organolithium species to a carbonyl group is one 10 unchanged of styrene oxide against the temperature and the of the most fundamental reactions in organic chemistry. In fact, it 22 logarithm of the residence time. 60 is well known that ketones react with organolithium species very rapidly, although ketones survive in the reactions of some In Figure 10 the yields of the methylated product 2 are plotted less reactive organometallics.23 Therefore, organic chemistry against the temperature and the logarithm of the residence time. textbooks say that a ketone carbonyl group should be protected 15 In a low temperature–short residence time region, the yield is low prior to an organolithium reaction if it is not involved in the because the starting material remained unchanged. The yield 65 desired transformation. Otherwise, the organolithium species increases with an increase in the temperature and the residence attacks the ketone carbonyl group. If organolithium chemistry time, but further increase in the temperature and the residence could be free from such limitation, its power will be greatly time causes a decrease in the yield because of decomposition of enhanced. This is indeed the case. Organolithium reactions 20 -phenyloxiranyllithium (1). without protecting the ketone carbonyl groups can be 70 accomplished based on the concept of flash chemistry. Free ketone carbonyl groups can survive in organolithium reactions within a very short reaction time. For example, aryllithium species bearing ketone carbonyl groups, which are generated by iodine–lithium exchange 75 reactions of the corresponding aryl iodides with mesityllithium, can be reacted with various electrophiles including aldehydes, chloroformates, and isocyanates using an integrated flow microreactor system (Figure 11). The residence time is a crucial factor and the transformation can be achieved only with a 80 residence time of 0.003 s or less. Long residence times lead to decomposition of the aryllithium species to give byproducts such as dimeric compounds. Figure 10. Contour plots with scatter overlay of the yield of the methylated product 2 against the temperature and the logarithm of the residence time. 25 It is important to note that the present temperature–residence time map is quite effective in revealing the stability and reactivity of highly reactive intermediates. Therefore, flow microreactor systems serve as powerful tools for mechanistic studies of 30 reactions invovling highly unstable intermediates. It is also noteworthy that the temperature–residence time maps serve as time efficient tools for optimizing reaction conditions. A map 85 consisting of 30–40 data points can be made in a day or two by Figure 11. Generation and reactions of aryllithium species collecting product solutions under various conditions and bearing ketone carbonyl groups 35 subsequent GC or LC analysis. In the following part, we will highlight some applications of To demonstrate the potential of the flow microreactor method, 24,25 flash chemistry to demonstrate how powerful this concept is and 90 we synthesized Pauciflorol F (3), a natural product isolated from stem bark (Figure 12). The I–Li exchange reaction of the

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iodoketone 4 to generate aryllithium bearing ketone 5 followed methyl ester (8) of TAC-101 (9)34, which is a synthetic retinoid by reaction with 3,5-dimethoxybenzaldehyde was conducted 40 with selective binding affinity for RAR- and its analogues in using a flow microreactor system (the residence time in R2: 0.003 good yields. The total residence time from 1,3,5-tribromobenzene s) to give the desired product 6 in 81% isolated yield (1.06 g for 5 to compound 8 was ca. 13 s, and the productivity of 8 was 100- 5 min operation). Presumably, dehydration took place upon the 200 mg/min. acidic work-up. Treatment with HCl/i-PrOH in the presence of O2 in a batch reactor gave the cyclopentenone derivative 7 in 75% yield, which is known to be converted to Pauciflorol F (3).

Figure 14. Synthesis of TAC-101 (7) using an integrated flow microreactor sytem.

50 A new approach to asymmetric synthesis Chiral organometallics35 provide powerful intermediates for 10 Figure 12. Synthesis of Pauciflorol F (3) using a flow the synthesis of enantioenriched compounds. In general, microreactor system. configurationally stable organometallics are used for highly enantioselective transformations, because the use of 36 Various organolitium species including aryllthium species 55 configurationally unstable organometallics usually leads to rapid epimerization before they can react with electrophiles, even 15 bearing electrophilic functional groups such as ketone and ester carbonyl groups,26 nitro group,27 and cyano group28 can be if such intermediates are produced enantioselectively. Flow successfully generated and be reacted with various electrophiles microreactor systems enable the rapid generation of in flow microreactor systems (Figure 13). o-Bromophenyllthium configurationally unstable organometallics, and allow their spcies, which rapidly undergo -elimination to give benzyne, can 60 reaction with electrophiles before they epimerize based on high- resolution control of the residence time. 20 also be generated and used for reactions with electrophile by adjusting the residence time.29 Perfluoroalkyllthium species, The addition of organolithium species to conjugated enyne 10 bearing a carbamoyl group as a directing group in the presence which are known to easily undergo - or -elimination can also of a chiral ligand such as sparteine to generate chiral be generated and used for reactions with electrophiles using flow 37 65 organolithium intermediate 11, and the subsequent reaction with microreactor sytems.30 Similary 1,2-dichlorovinyllithium can be electrophiles using an integrated flow microreactor system was 25 immediately reacted with electrophiles, although it undergoes - studied (Figure 15).38 Organolithium intermediate 11 quickly elimination with a longer residence time at higher temperatures.31 undergoes epimerization and the success of enantioselective

synthesis relies on the control of the residence time in R2 70 microreactor R2 (t ) to avoid the epimerization.

30 Figure 13. Unstable organolithium species

Multi-step synthesis Figure 15. Asymmetric carbolithiation of a conjugated enyene. The concept of flash chemistry is applicable to multi-step 75 synthesis. Sequential introduction of three electrophiles into As profiled in Figure 16 the yield of the product 12 obtained 35 1,3,5-tribromobenzene based on Br/Li exchange reaction was + + 32 by using methanol as an electrophile (E = H ) increased with achieved using an integrated flow microreactor system increasing tR and temperature. In contrast, the enantiomeric consisting of six micromixers and six microtube reactors as composition (ec) decreased with increasing tR2 and temperature, 33 shown in Figure 14. This method enables flash synthesis of 80 presumably because of epimerization of the intermediate 11. This

result means that the decrease of enantiomeric composition For example, a solution of Pd(OAc)2 and that of t-Bu3P were resulted from epimerization of the lithiated species rather than its introduced to a micromixer and the resulting solution was passed formation step. The residence time–temperature domain that gave through a microtube reactor (the residence time: 0.65 s). After a both a high yield (>90%) and a high ec (>90%) was very small. 50 steady state was reached, the resulting solution was dropped into 5 However, it is noteworthy that when we carried out the reaction a vessel containing a solution of p-bromotoluene, phenylboronic in this domain (e.g., residence time: 25 s, Temperature: –78 C), the desired product, the enantioenriched allene 12 was obtained in acid, and potassium hydroxide. After addition was complete, the a high yield (91%) with a high selectivity (91% ec). In contrast, mixture in the reaction vessel was stirred at room temperature, the reaction using a batch macro reactor (reaction time: 25 s, and the progress of the coupling reaction was monitored by GC o 10 Temperature: –78 C) gave the product in 99% yield with a low 55 (Figure 17). selectivity (61% ec). Batch reactions under several conditions For comparison, three conventional methods were examined. also led to low ec. Under the optimized conditions, various In method A, a solution of t-Bu3P in THF was added to a reaction enantioenriched allenes were successfully synthesized in flow. vessel, and after 10 s, a solution of Pd(OAc)2 in THF was added. In method B, a solution of Pd(OAc)2 was added, and after 10 s, a 60 solution of t-Bu3P was added. In method C, both solutions were added simultaneously to a reaction vessel (10 s). In all cases, 1 mol% of Pd(OAc)2 and 1 mol% of t-Bu3P based on p- bromotoluene were introduced to the reaction vessel. Notably, the catalytic activity strongly depends on the way of addition of 65 Pd(OAc)2 and t-Bu3P. As shown in Figure 17, the reaction was complete within 5 min in the case of the flash method. However, in all conventional methods the reaction took much longer time to reach completion. The extremely high reactivity observed for the catalyst generated by the flash method seems to be attributed to 70 the quick generation of a highly unstable reactive catalyst precursor by fast micromixing of Pd(OAc)2 and t-Bu3P in the absence of coupling substrates and potassium hydroxide, and its transfer to the reaction vessel before it decomposes by virtue of the short residence time in the flow system. 75

Figure 16. Temperature–residence time (in R2) map for the reaction of enyne in the presence of sparteine. A contour plot with scatter overaly of enantionmeric composition (ec) (upper) + + 20 and that of the yield (lower) of protonated product (E = H ), and the domain that gave both high ec (>90%) and high yield (>90%) (middle).

A new approach to catalyst generation 25 In the previous sections we discussed generation and reactions of highly unstable reactive species by taking advantage of high- resolution residence time control using flow microreactors. This concept can be applied to generation of highly reactive short- lived catalyst before it decomposes. The following example 30 demonstrates that the concept has been successfully applied to the generation of an extremely efficient Pd catalyst for Suzuki– Miyaura coupling.39,40,41 It is well known that generation of monoligated [Pd(0)L] species (L = phosphine ligand) plays an important role in the 35 Suzuki–Miyaura coupling reactions, because coordinatively unsaturated [Pd(0)L] species are highly reactive towards oxidative addition of aryl halides (ArX) to produce [Pd(Ar)X(L)], a key intermediate in the coupling.42 However, [Pd(0)L] is highly unstable and its generation at high concentrations is very difficult. 40 The flash method involving 1:1 mixing of Pd(II) and L in flow microreactor enables the generation of unstable monoligated [Pd(II)L] species as a precursor at high concentrations in the Figure 17. Suzuki–Miyaura coupling of p-bromotoluene and absence of coupling substrates. In the next step, [Pd(II)L] species phenylboronic acid in the presence of KOH catalyzed by is transferred, before it decomposes, to a reaction vessel for 80 [Pd(OAc)2]–t-Bu3P. 45 coupling reactions, where it may be reduced to give highly

reactive [Pd(0)L].

An in-line flow FT-IR spectroscopic analysis (ATR method)43 Conclusions indicated the formation of [Pd(OAc)2－t-Bu3P]2 (13) by fast 1:1 55 The examples shown in this article and many other examples in micromixing of Pd(OAc)2 and t-Bu3P in the flow microreactor the literature illustrate the potential of flash chemistry using flow system, although an increase in the residence time caused its microreactors in chemical science and chemical production. Flash 5 decomposition to give the less active palladacycle 14 (Figure 18). chemistry serves as powerful method for protecting group free The quick transfer of highly active 13 to the reaction vessel leads synthesis, multi-step synthesis, asymmetric synthesis, and to extremely fast Suzuki–Miyaura coupling. The coupling 60 generation of highly reactive catalysts. It is hoped that various reactions could be complete within 5 min even at room types of applications of flash chemistry will be developed and temperature. Aryl- or heteroarylboronic acids, which quickly widely utilized in laboratories and industries to meet future 10 deboronate under basic conditions, could be also used as coupling demands for highly efficient chemical synthesis and production. partners, because the reactions can be conducted at lower

temperatures and in a short time. 65 Acknowledgements

This work was financially supported in part by the Grant-in- Aid for Scientific Research on Innovative Areas (No. 2015) from 70 the MEXT.

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